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Anandamide-derived Prostamide F2α Negatively Regulates Adipogenesis

C. Silvestri,A. Martella,N. Poloso,F. Piscitelli,R. Capasso,A. Izzo,D. Woodward,V. Di Marzo

Published 2013 in Journal of Biological Chemistry

ABSTRACT

Background: Adipogenesis is the process by which adipocytes are formed to maintain or expand fat depots. Results: Prostaglandin F2α ethanolamide (PGF2αEA) is produced from anandamide in preadipocytes and inhibits adipogenesis. Conclusion: Conversion of proadipogenic anandamide to antiadipogenic PGF2αEA is a novel mechanism for the regulation of adipogenesis. Significance: Discovering a PGF2αEA-mediated negative regulatory mechanism over adipogenesis may lead to the development of antiobesity therapies. Lipid mediators variedly affect adipocyte differentiation. Anandamide stimulates adipogenesis via CB1 receptors and peroxisome proliferator-activated receptor γ. Anandamide may be converted by PTGS2 (COX2) and prostaglandin F synthases, such as prostamide/prostaglandin F synthase, to prostaglandin F2α ethanolamide (PGF2αEA), of which bimatoprost is a potent synthetic analog. PGF2αEA/bimatoprost act via prostaglandin F2αFP receptor/FP alt4 splicing variant heterodimers. We investigated whether prostamide signaling occurs in preadipocytes and controls adipogenesis. Exposure of mouse 3T3-L1 or human preadipocytes to PGF2αEA/bimatoprost during early differentiation inhibits adipogenesis. PGF2αEA is produced from anandamide in preadipocytes and much less so in differentiating adipocytes, which express much less PTGS2, FP, and its alt4 splicing variant. Selective antagonism of PGF2αEA receptors counteracts prostamide effects on adipogenesis, as does inhibition of ERK1/2 phosphorylation. Selective inhibition of PGF2αEA versus prostaglandin F2α biosynthesis accelerates adipogenesis. PGF2αEA levels are reduced in the white adipose tissue of high fat diet-fed mice where there is a high requirement for new adipocytes. Prostamides also inhibit zebrafish larval adipogenesis in vivo. We propose that prostamide signaling in preadipocytes is a novel anandamide-derived antiadipogenic mechanism.

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